Studying the mechanism(s) of uterine relaxation is important and will be helpful in the prevention of obstetric difficulties such as preterm labour, which remains a major cause of perinatal mortality and morbidity. Multiple signalling pathways regulate the balance between maintaining relative uterine quiescence during gestation, and the transition to the contractile state at the onset of parturition. Elevation of intracellular cyclic AMP promotes myometrial relaxation, and thus quiescence, via effects on multiple intracellular targets including calcium channels, potassium channels and myosin light chain kinase. A complete understanding of cAMP regulatory pathways (synthesis and hydrolysis) would assist in the development of better tocolytics to delay or inhibit preterm labour. Here we review the enzymes involved in cAMP homoeostasis (adenylyl cyclases and phosphodiesterases) and possible myometrial substrates for the cAMP dependent protein kinase. We must emphasise the need to identify novel pharmacological targets in human pregnant myometrium to achieve safe and selective uterine relaxation when this is indicated in preterm labour or other obstetric complications.

Developmental exposure to unrelated neurotoxicants can nevertheless converge on common final targets so as to exacerbate damage or functional deficits. We examined the effects of developmental exposure to terbutaline, a β2-adrenergic receptor agonist used to arrest preterm labor, and chlorpyrifos, a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and chlorpyrifos (5 mg/kg) on PN11-14, with assessments conducted in juvenile and adolescent stages (PN21, PN30 and PN45), comparing each agent alone as well as sequential administration of both. By itself, terbutaline produced persistent 5HT presynaptic hyperactivity as evidenced by increased 5HT turnover in brain regions containing 5HT terminal zones; this effect was similar to that seen in earlier studies with chlorpyrifos administration during the same early postnatal period. Later administration of chlorpyrifos (PN11-14) produced a transient increase in 5HT turnover during the juvenile stage, and the sequential exposure paradigm, terbutaline followed by chlorpyrifos, showed a corresponding increase in effect over either agent alone. In combination with our earlier work on 5HT receptors...

We report a case of diamniotic, dichorionic pregnancy presented at 24 weeks with premature rupture of the first amnionic sac. Seven days later, premature labour and delivery of the first twin took place, with unfortunate outcome. The second twin was left in utero. The management included combination of tocolytics, antibiotics and cervical cerclage. Caesarean section was performed 48 days later, at 32 weeks and we delivered a live male infant, successfully.

Better tocolytics are required to help prevent preterm labour. The gaseotransmitter Hydrogen sulphide (H2S) has been shown to reduce myometrial contractility and thus is of potential interest. However previous studies used NaHS, which is toxic and releases H2S as a non-physiological bolus and thus alternative H2S donors are sought. GYY4137 has been developed to slowly release H2S and hence better reflect endogenous physiological release. We have examined its effects on spontaneous and oxytocin-stimulated contractility and compared them to NaHS, in human and rat myometrium, throughout gestation. The effects on contractility in response to GYY4137 (1 nM–1 mM) and NaHS (1 mM) were examined on myometrial strips from, biopsies of women undergoing elective caesarean section or hysterectomy, and from non-pregnant, 14, 18, 22 day (term) gestation or labouring rats. In pregnant rat and human myometrium dose-dependent and significant decreases in spontaneous contractions were seen with increasing concentrations of GYY4137, which also reduced underlying Ca transients. GYY4137 and NaHS significantly reduced oxytocin-stimulated and high-K depolarised contractions as well as spontaneous activity. Their inhibitory effects increased as gestation advanced...

Background: Prenatal stress seems to have long-lasting effects on biological and psychological processes of the offspring. However, to date, there have been no studies investigating the effects of prenatal glucocorticoid exposure on psychological, endocrine, and autonomic responses to a standardized psychosocial stress test in children. Methods: A sample of 115 healthy, 10-year-old children was examined. The Glucocorticoids + Tocolytics group was characterized by tocolytic treatment of the mothers due to preterm labor (n = 43). In addition, the pregnant women received glucocorticoid treatment in order to accelerate fetal lung maturation in case of preterm birth. The first comparison group (Tocolytics) consisted of children whose mothers also experienced preterm labor, but did not receive glucocorticoid treatment (n = 35). In the second comparison group (CONTROL), children whose mothers had a complication-free pregnancy were assessed (n = 37). Psychological parameters (stress appraisal and mood) using self-report questionnaires as well as salivary cortisol, salivary alpha-amylase, and heart rate were measured during a standardized psychosocial stress test (Trier Social Stress Test for Children). Results: Group comparisons revealed that a subscale of stress appraisal...

Preterm delivery is a public health issue of major proportion. More than 12% of deliveries in the United States that occur at less than 37 weeks gestation preterm labor (PTL) represents the largest single reason for preterm birth (PTB). Attempts to prevent PTB have been unsuccessful. This paper of maintenance tocolytic therapy will examine the efficacy and safety of the drugs, both oral and subcutaneous, which have been utilized for prolongation of pregnancy following successful arrest of a documented episode of acute preterm labor. The evidence for oral tocolytics as maintenance therapy as well as parenteral medications for such patients is offered. Finally, the effects in the United States of the Food and Drug Administration (FDA) action on such medications are reported.

The aim of this paper is to provide a thorough summary of published studies that have assessed the efficacy of adjunctive therapies used in addition to cervical cerclage as a preventive measure for preterm birth. We limited our paper to patients treated with cerclage plus an additional prophylactic therapy compared to a reference group of women with cerclage alone. The specific adjunctive therapies included in this systematic review are progesterone, reinforcing or second cerclage placement, tocolytics, antibiotics, bedrest, and pessary. We searched PubMed and Cochrane databases without date criteria with restriction to English language and human studies and performed additional bibliographic review of selected articles and identified 305 total studies for review. Of those, only 12 studies compared the use of an adjunctive therapy with cerclage to a reference group of cerclage alone. None of the 12 were prospective randomized clinical trials. No comparative studies were identified addressing the issues of antibiotics, bedrest, or pessary as adjunctive treatments to cerclage. None of the 12 studies included in this paper demonstrated a clear benefit of any adjunctive therapy used in addition to cerclage over and above cerclage used alone; however...

Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis.

In the past decades, we have observed a large increase in the number of multifetal pregnancies, which is mainly associated with the introduction of assisted reproductive techniques. Even though neonatal intensive care of very premature infants has improved significantly, the risk of mortality and long-term morbidity is still much higher among these newborns. A longer interdelivery period may reduce perinatal mortality and morbidity. The authors report the case of a delayed interval delivery in trichorionic, triamniotic triplet pregnancy. After the labor of the first fetus in the 22nd week of gestation, a 75-day interval was achieved before the delayed delivery. To save the surviving fetuses, the umbilical cord was ligated at the cervical level immediately after the first delivery. The patient received antibiotics, tocolytics, and corticosteroids. A baby boy who weighed 1750 g and a girl who weighed 1700 g were successfully delivered by cesarean section in the 33rd week of pregnancy. The babies were discharged home at the age of 28 days. A follow-up examination 20 weeks later showed that their neurological development was normal and without any major problems. The maternal postpartum course was uneventful; the patient stayed in hospital taking care of the babies.

In this review we overview the mechanisms responsible for uterine contractility and relaxation. We then use this as the basis for discussing the two major uterotonins, oxytocin and prostaglandins followed by currently available (although often unlicensed) tocolytics; progesterone, magnesium, calcium channel blockers, oxytocin receptor blockers, β-adrenergic receptor agonists, prostaglandin synthesis inhibitors and nitric oxide donors. In this brief review we have concentrated on the most important mechanisms of action and data obtained on human tissue. By focussing on mechanisms, meta-analyses and Cochrane literature reviews, our aim is to provide insight for clinical usefulness, and highlight where further research is required and where the targets may be.

Breech presentation is encountered in 3 to 4% of term pregnancies and has been a significant driver of the increased rate of cesarean deliveries over the last 4 decades. External cephalic version (ECV) is recommended at term by most professional organizations in an effort to reduce the prospect of cesarean deliveries. The authors propose the use of regional anesthesia to increase efficacy and reduce cost in the care of patients who undergo ECV in an effort to convert a breech presentation to a vertex counterpart. Despite emerging evidence of the advantages, obstacles to more comprehensive implementation of this approach continue to exist, which include patient acceptance, provider experience, and safety concerns. The addition of tocolytics and use of regional anesthesia for secondary ECV efforts have also been considered as options to increase success and reduce cost. This is a commentary on http://www.ijhpr.org/content/3/1/5.

Administration of short-term tocolytic agents can prolong pregnancy for women in preterm labor. Prolonging pregnancy has many benefits because it allows for other proven interventions, such as antenatal corticosteroid administration, to be accomplished. This review provides an overview of currently utilized tocolytic agents and the evidence demonstrating their efficacy for prolonging pregnancy by at least 48 hours. General pharmacological principles for the clinician regarding drugs in pregnancy are also briefly discussed. In general, while the choice of the best first-line short-term tocolytic drug is not clear, it is evident that use of these agents has a clear place in current obstetric therapeutics.

The uterus and heart share the important physiological feature whereby contractile activation of the muscle tissue is regulated by the generation of periodic, spontaneous electrical action potentials (APs). Preterm birth arising from premature uterine contractions is a major complication of pregnancy and there remains a need to pursue avenues of research that facilitate the use of drugs, tocolytics, to limit these inappropriate contractions without deleterious actions on cardiac electrical excitation. A novel approach is to make use of mathematical models of uterine and cardiac APs, which incorporate many ionic currents contributing to the AP forms, and test the cell-specific responses to interventions. We have used three such models—of uterine smooth muscle cells (USMC), cardiac sinoatrial node cells (SAN), and ventricular cells—to investigate the relative effects of reducing two important voltage-gated Ca currents—the L-type (ICaL) and T-type (ICaT) Ca currents. Reduction of ICaL (10%) alone, or ICaT (40%) alone, blunted USMC APs with little effect on ventricular APs and only mild effects on SAN activity. Larger reductions in either current further attenuated the USMC APs but with also greater effects on SAN APs. Encouragingly...

ABSTRACT Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations. DESIGN Prospective cohort study. SETTING 28 hospitals in the Netherlands and Belgium. PARTICIPANTS 1920 consecutive women treated with tocolytics for threatened preterm labour. MAIN OUTCOME MEASURES Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment. RESULTS An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a β adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drug tocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation...

BACKGROUND: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects. METHODS/DESIGN: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery...

BACKGROUND: Evidence summaries of tocolytic effectiveness assign quality levels based on a single dimension: the study design. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system takes into account several domains, including limitations of the study design and ranking the importance of outcomes. OBJECTIVES: The aim of the study was to compare the quality of evidence according to GRADE with the quality as described by existing guidelines. SEARCH STRATEGY: A practitioner survey to rank the importance of outcomes and a systematic review were conducted. For the systematic review, we searched Medline, Embase, and DARE databases from inception to December 2010 using the terms 'tocolytics' and 'threatened preterm labour', without any language restrictions. SELECTION CRITERIA: Inclusion criteria for the review were randomised controlled trials comparing tocolytics with either placebo or betamimetics. DATA COLLECTION AND ANALYSIS: The review and survey teams worked independently. Evidence ratings according to GRADE were performed. MAIN RESULTS: The majority of the survey respondents thought that it was important to use tocolytics to buy the time needed for steroids to promote fetal lung maturation and to allow in utero transfer. Nearly 80% of 'high' ratings in guidelines were downgraded as a result of deficiencies identified by GRADE. AUTHORS' CONCLUSIONS: We propose a move away from the use of evidence rating systems reliant solely on study design...

INTRODUCTION: In the developed world, preterm birth is in quantity and in severity the most important issue in obstetric care. Adverse neonatal outcome is strongly related to gestational age at delivery. Since the pathophysiological mechanism of preterm birth is not yet completely unraveled, the development of successful preventive strategies is hampered. When preterm labor is actually threatening, current pharmacological therapies focus on inhibition of preterm contractions. This allows for transportation of the mother to a center with a neonatal intensive care unit and administration of corticosteroids to enhance fetal lung maturation. Globally, however, large practice variation exists. AREAS COVERED: The aim of this review is to provide an overview of current pharmacological therapies for preterm labor. EXPERT OPINION: For the initial tocolysis, the use of atosiban or nifedipine for 48 h is recommended based on the largest effectiveness and most favorable side effect profile. However, since data that convincingly indicate the beneficial effect of tocolytics on neonatal outcome are lacking, it might well be that tocolytics are ineffective. The role of progesterone in treatment of acute tocolysis is limited, but it might play a role in the prevention of preterm labor or as sensitizer for other tocolytic agents.; Elvira OG van Vliet...